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WO2024109937A1 - 一种喹啉胺类化合物的可药用盐、晶型及其制备方法 - Google Patents

一种喹啉胺类化合物的可药用盐、晶型及其制备方法 Download PDF

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WO2024109937A1
WO2024109937A1 PCT/CN2023/134049 CN2023134049W WO2024109937A1 WO 2024109937 A1 WO2024109937 A1 WO 2024109937A1 CN 2023134049 W CN2023134049 W CN 2023134049W WO 2024109937 A1 WO2024109937 A1 WO 2024109937A1
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ray powder
compound
characteristic peaks
powder diffraction
diffraction pattern
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PCT/CN2023/134049
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English (en)
French (fr)
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杨俊然
杜振兴
王捷
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2024109937A1 publication Critical patent/WO2024109937A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the chemical ratio of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine to the acid molecule is 1:0.5 to 1:3, including 1:0.5, 1:1, 1:2 or 1:3.
  • the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine is separated from the acid
  • the chemical ratio of the seeds is 1:0.5 or 1:1.
  • the present disclosure also provides a method for preparing a pharmaceutically acceptable salt of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, comprising the step of forming a salt of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine with an acid.
  • the acid used in the salt-forming reaction is selected from p-toluenesulfonic acid, phosphoric acid, sulfuric acid, maleic acid, hydrobromide and hydrochloric acid.
  • the present disclosure also provides a crystalline form I of the p-toluenesulfonate salt of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 6.616, 8.996, 14.120, 19.138 and 22.592.
  • the p-toluenesulfonate salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.616, 8.996, 13.304, 14.120, 17.120, 19.138, 20.615, 21.289, 22.592, 25.033, 26.101 and 26.503.
  • the p-toluenesulfonate salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG1 .
  • the present disclosure also provides a phosphate crystal form I of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 6.511, 9.685, 12.660, 14.012 and 15.704.
  • the phosphate I crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.511, 9.685, 12.660, 14.012, 15.704, 16.517, 21.487 and 22.209.
  • the phosphate I crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.511, 9.685, 12.660, 14.012, 15.704, 16.517, 18.507, 21.487, 22.209, 24.493 and 25.596.
  • the X-ray powder diffraction pattern of the phosphate I crystal form represented by a diffraction angle of 2 ⁇ is shown in Figure 2.
  • the present disclosure also provides a method for preparing the phosphate I crystal form of the aforementioned compound, comprising the steps of mixing the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine and a solvent (2), (b) adding phosphoric acid, and crystallizing, wherein the solvent (2) is selected from acetonitrile.
  • the present disclosure also provides a sulfate salt crystalline form I of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 5.687, 11.448, 14.670, 17.315, 23.323 and 24.907.
  • the sulfate salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.687, 9.540, 11.448, 14.670, 17.315, 18.906, 23.323 and 24.907.
  • the sulfate salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.687, 9.540, 11.448, 12.137, 14.670, 17.315, 17.465, 18.906, 21.682, 23.323 and 24.907.
  • the X-ray powder diffraction pattern of the sulfate salt form I represented by a diffraction angle of 2 ⁇ is shown in FIG3 .
  • the present disclosure also provides a method for preparing the sulfate salt I crystal form of the aforementioned compound, comprising the steps of mixing the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine and a solvent (3), (b) adding sulfuric acid, and crystallizing, wherein the solvent (3) is selected from ethanol or acetone.
  • the present disclosure also provides a sulfate salt II crystalline form of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 11.895, 13.102, 15.607, 16.658 and 17.967.
  • the sulfate II crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.518, 11.895, 13.102, 15.607, 16.181, 16.658, 17.967 and 24.329.
  • the sulfate II crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.518, 10.808, 11.291, 11.895, 13.102, 15.196, 15.607, 16.181, 16.658, 17.967 and 24.329.
  • the X-ray powder diffraction pattern of the sulfate II crystal form represented by a diffraction angle of 2 ⁇ is shown in FIG. 4 .
  • the present disclosure also provides a method for preparing the sulfate II crystal form of the aforementioned compound, comprising the steps of mixing the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine and a solvent (4), (b) adding sulfuric acid, and crystallizing, wherein the solvent (4) is selected from acetonitrile.
  • the present disclosure also provides a sulfate salt III crystalline form of compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 13.502, 16.610, 17.858, 22.247 and 26.671.
  • the sulfate III crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.675, 13.502, 16.610, 17.858, 22.247, 25.379, 26.671 and 27.029.
  • the sulfate III crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.675, 13.502, 16.610, 17.449, 17.858, 22.247, 24.292, 25.379, 26.671 and 27.029.
  • the X-ray powder diffraction pattern of the sulfate III crystal form represented by a diffraction angle of 2 ⁇ is shown in FIG5 .
  • the present disclosure also provides a method for preparing the sulfate III crystal form of the aforementioned compound, comprising the steps of mixing the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine and a solvent (5), (b) adding sulfuric acid, and crystallizing, wherein the solvent (5) is selected from a mixed solution of water and methanol.
  • the present disclosure also provides a compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine.
  • the X-ray powder diffraction pattern of the salt form I expressed in terms of a diffraction angle of 2 ⁇ , has characteristic peaks at 8.101, 12.810, 16.435, 26.186 and 27.616.
  • the maleate salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.101, 12.810, 16.435, 20.667, 25.309, 26.186 and 27.616.
  • the maleate salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.101, 12.810, 14.598, 16.435, 20.667, 21.474, 22.460, 25.309, 26.186 and 27.616.
  • the maleate salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG6 .
  • the present disclosure also provides a method for preparing the maleate salt I crystalline form of the aforementioned compound, comprising the steps of mixing the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine and a solvent (6), (b) adding maleic acid, and crystallizing, wherein the solvent (6) is selected from ethanol.
  • the present disclosure also provides a maleate II crystalline form of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 7.817, 8.777, 11.663, 16.222 and 26.051.
  • the maleate II crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.817, 8.777, 11.663, 12.691, 16.222, 21.791 and 26.051.
  • the maleate II crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.817, 8.451, 8.777, 11.663, 12.691, 15.028, 16.222, 17.399, 21.791 and 26.051.
  • the maleate II crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 7 .
  • the present disclosure also provides a method for preparing the maleate II crystalline form of the aforementioned compound, comprising the steps of mixing the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine and a solvent (7), (b) adding maleic acid, and crystallizing, wherein the solvent (7) is selected from at least one of acetonitrile, ethanol, methanol or water.
  • the present disclosure also provides a hydrobromide salt form I of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 6.077, 12.258, 22.769, 24.662 and 26.579.
  • the hydrobromide salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.077, 12.258, 22.769, 24.662, 25.696, 26.579 and 34.105.
  • the hydrobromide salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.077, 12.258, 16.589, 20.396, 22.769, 24.662, 25.218, 25.696, 26.579 and 34.105.
  • the hydrobromide salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG8 .
  • the present disclosure also provides a method for preparing the hydrobromide salt of the aforementioned compound in crystalline form I, comprising the steps of mixing the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine and a solvent (8), (b) adding hydrobromic acid, and crystallizing, wherein the solvent (8) At least one selected from ethanol, acetonitrile or acetone.
  • the present disclosure also provides a hydrochloride salt form I of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 13.229, 14.520, 18.561, 19.925 and 23.830.
  • the hydrochloride salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 13.229, 14.520, 18.561, 19.925, 23.830, 24.603 and 25.325.
  • the hydrochloride salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 13.229, 14.520, 18.561, 19.925, 21.085, 22.588, 23.830, 24.603, 25.325 and 26.708.
  • the X-ray powder diffraction pattern of the hydrochloride salt form I represented by a diffraction angle of 2 ⁇ is shown in FIG9 .
  • the present disclosure also provides a method for preparing the hydrochloride salt form I of the aforementioned compound, comprising the steps of mixing the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine and a solvent (9), (b) adding hydrochloric acid, and crystallizing, wherein the solvent (9) is selected from at least one of ethanol, acetonitrile or acetone.
  • the present disclosure also provides a hydrochloride salt II crystalline form of the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 11.888, 13.593, 17.851, 23.977 and 26.309.
  • the hydrochloride salt II crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 11.888, 13.593, 17.851, 19.114, 23.977, 25.878 and 26.309.
  • the hydrochloride salt II crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 11.888, 13.593, 14.492, 17.851, 19.114, 20.367, 23.977, 25.878, 26.309 and 29.779.
  • the X-ray powder diffraction pattern of the hydrochloride salt II crystal form represented by a diffraction angle of 2 ⁇ is shown in FIG. 10 .
  • the present disclosure also provides a method for preparing the hydrochloride II crystal form of the aforementioned compound, comprising the steps of mixing the compound 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine and a solvent (10), (b) adding hydrochloric acid, and crystallizing, wherein the solvent (10) is selected from at least one of ethanol, methanol or water.
  • the present invention discloses an X-ray powder diffraction pattern of the aforementioned compound crystal form represented by a diffraction angle 2 ⁇ , wherein the error range of the 2 ⁇ angle is ⁇ 0.2.
  • the method for preparing the crystalline form described in the present disclosure further comprises any step of stirring and dissolving or heating and dissolving, filtering, washing or drying.
  • the crystallization includes but is not limited to stirring crystallization (dissolution crystallization, slurry crystallization) and volatile crystallization.
  • the drying method includes but is not limited to forced air drying and vacuum drying.
  • the drying temperature is generally 25°C to 100°C, preferably 30°C to 70°C, such as 40°C, 50°C or 60°C.
  • the present disclosure also provides a pharmaceutical composition, which includes the aforementioned crystal form and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a pharmaceutical composition prepared from the aforementioned crystal form and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form with a pharmaceutically acceptable excipient.
  • the present disclosure also provides use of the aforementioned crystal form or pharmaceutical composition in the preparation of a drug for regulating miRNA levels; preferably, the miRNA is miR-124.
  • the present disclosure also provides use of the aforementioned crystalline form or pharmaceutical composition in a drug for treating and/or preventing a disease or condition, wherein the disease or condition is selected from inflammation and cancer.
  • the inflammation is inflammatory bowel disease.
  • the cancer is melanoma or breast cancer.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • the "differential scanning calorimetry or DSC” described in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
  • the drying temperature in the present disclosure is generally 25°C-100°C, preferably 30°C-70°C, and the drying can be carried out under normal pressure or reduced pressure.
  • compositions include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals.
  • the "beating” mentioned in the present disclosure refers to a method of purification that utilizes the property that a substance has poor solubility in a solvent, but impurities have good solubility in a solvent. Beating purification can remove color, change the crystal form, or remove a small amount of impurities.
  • the crystalline forms disclosed herein include but are not limited to solvates of Compound 1, and the solvents include but are not limited to water.
  • Figure 1 is an XRPD diagram of p-toluenesulfonate Form I.
  • Figure 2 is an XRPD diagram of phosphate I crystal form.
  • Figure 3 is the XRPD diagram of sulfate I crystal form.
  • FIG. 4 is an XRPD diagram of sulfate II crystal form.
  • Figure 5 is the XRPD diagram of sulfate III crystal form.
  • FIG. 6 is an XRPD diagram of maleate salt Form I.
  • FIG. 7 is an XRPD diagram of maleate II crystal form.
  • FIG8 is an XRPD diagram of hydrobromide salt Form I.
  • FIG. 9 is an XRPD diagram of hydrochloride salt Form I.
  • FIG. 10 is an XRPD diagram of the hydrochloride salt Form II.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using Agilent 1200/1290DAD-6110/6120 Quadrupole MS LC-MS (Manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (Manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q 15 Exactive).
  • HPLC determinations were performed using an Agilent 1260DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6 mm column) and a Thermo U3000 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6 mm column).
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), ray: monochromatic Cu-Ka ray Scanning mode: ⁇ /2 ⁇ , scanning range: 3-48°.
  • DSC is differential scanning calorimetry: the measurement was carried out using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C/min, 25-300°C, and a nitrogen purge rate of 50mL/min.
  • TGA thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C/min.
  • the specific temperature range refers to the corresponding spectrum, and the nitrogen purge rate is 50mL/min.
  • DVS dynamic moisture adsorption: using Surface Measurement Systems instrument, humidity starts from 50%, the humidity range is 0%-95%, the step is 10%, the judgment standard is each gradient mass change dM/dT ⁇ 0.002%, TMAX 360min, two cycles.
  • the known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • Example 1 Synthesis of 8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quin-2-amine (refer to the preparation method of Example 1 in application No. WO2022247920)
  • 2,8-Dichloroquinoline 1a (100 mg, 0.51 mmol, Bidex Pharmaceuticals) and 5-amino-2,2-difluoro-1,3-benzo[1,3]dioxolane 1b (105 mg, 0.61 mmol, Shanghai Haohong) were dissolved in isopropanol (1 mL) and heated to 90 °C for 12 hours. The reaction solution was filtered and then subjected to high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: 0.1% formic acid aqueous solution and acetonitrile, acetonitrile gradient: 65%-85%, flow rate: 30 mL/min) to obtain the title compound 1 (150 mg, yield 89.0%).
  • Human interleukin 2 Human IL-2 (Peprotech, 200-02-100)
  • RNA extraction kit (microRNA extraction kit) (Qiagen, 217004)
  • Phosphate buffer PBS pH 7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320)
  • RPMI1640 culture medium (Gibco, 11875119)
  • Magnetic bead separation rack (QuadroMACS Separator) (Miltenyi Biotec, 130-090-976)
  • the effect of the compound on the expression level of miR-124 was detected in T cells activated by CD3/CD28 antibodies. After the activated T cells were treated with the compound, the total RNA of the cells was extracted, and the cDNA obtained by reverse transcription was used as a template for quantification using SYBR green fluorescent quantitative PCR method using specific miR-124 primers.
  • T cells Purchased human peripheral blood mononuclear cells (PBMC), counted and filtered, washed once with separation buffer (PBS pH 7.4, containing 0.5% BSA and 2mM EDTA), discarded the supernatant, added 40 ⁇ L buffer and 10 ⁇ L T cell separation biotinylated mixed antibody (pan T Cell Biotin-Antibody Cocktail) per 1 ⁇ 10 7 cells, added each component to resuspend the precipitate and mixed, and incubated in a refrigerator at 4°C for 5 minutes.
  • separation buffer PBS pH 7.4, containing 0.5% BSA and 2mM EDTA
  • T cell separation biotinylated mixed antibody pan T Cell Biotin-Antibody Cocktail
  • Activation of T cells Add 25 ⁇ L of activated magnetic beads per 1 ⁇ 10 6 cells, take out the corresponding T cell activation CD3/CD28 magnetic beads and put them in a 1.5 mL filter tube. Oscillate on the oscillator for about 30 seconds before aspirating. Wash the activated magnetic beads 3 times with culture medium in a volume ratio greater than 1:1 in the filter tube. Remove all the washing solution in the last time and add complete culture medium equal to the starting volume to resuspend the activated magnetic beads. Add the washed activated magnetic beads to the cell resuspension and mix well. Take out the six-well plate, add cells at 3 mL per well, and culture in a cell culture incubator at 37°C and 5% CO 2 for 2 days.
  • Compound treatment The compound stock solution is 20mM, diluted to 200 ⁇ M with DMSO, and then diluted 4 times to 50 ⁇ M (50 ⁇ ) with complete medium, mix well for use. DMSO diluted 4 times (25% DMSO) is the negative control well.
  • DMSO diluted 4 times (25% DMSO) is the negative control well.
  • Activate T cells for two days blow the cells evenly, use a magnetic stand and install a 1.5mL filter tube, remove the activated magnetic beads, and collect the cell suspension. After counting the cells, filter at 300xg, 10min and discard the supernatant, resuspend the cells to 1.02 ⁇ 10 6 /mL, add 980 ⁇ L of cell suspension and 20 ⁇ L of 50 ⁇ compound to each 24-well plate, and the final concentration of the compound is 1 ⁇ M. Place the cells in a 37°C, 5% CO 2 cell culture incubator and continue to culture for 3 days.
  • RNA extraction Collect T cells by filtration, filter at 1500 rpm for 3 minutes, wash once with PBS, and discard the supernatant after filtration. Extract total RNA from cells using the extraction kit according to the instructions. Add 700 ⁇ L Trizol cell lysis buffer to the cell pellet, blow evenly with a pipette tip, and place at room temperature for 5 minutes. Add 140 ⁇ L chloroform, shake and mix, and place at room temperature for 3 minutes. Filter the chloroform-cell lysis buffer mixture at 12000xg for 15 minutes at 4°C. Transfer the upper solution to a new RNase-free filter tube, add 1.5 times the volume of anhydrous ethanol, and blow several times with a pipette tip.
  • RNA adsorption column and filter at 8000xg for 15s Wash the filter column once with 700 ⁇ L RWT solution, filter at 8000xg for 15s, add 500 ⁇ L RPE solution and wash twice, and filter at 8000xg for 2 minutes. Place the adsorption column in a new 2mL filter tube and filter at 12000xg for 1min to remove the residual washing solution. Place the adsorption column in a new 1.5 mL filter tube, add 30-50 ⁇ L RNase-free water, filter at 12000 x g for 2 minutes, collect the RNA solution, and measure the RNA concentration using a spectrophotometer. The RNA solution is stored in a -80 degree refrigerator.
  • Reverse transcription Place the extracted RNA template on ice, take out the small RNA reverse transcription kit, thaw some components (including 5 ⁇ miScript HiSpec Buffer, 10 ⁇ miScript nucleics Mix and RNase-free water) at room temperature, and thaw the miScript Reverse Transcriptase mix components on ice.
  • Each reaction (10 ⁇ L) contains: 5 ⁇ miScript HiSpec Buffer (2 ⁇ L), 10 ⁇ miScript nucleics Mix (1 ⁇ L), miScript Reverse Transcriptase mix (1 ⁇ L), RNase-free water (2 ⁇ L), RNA template (4 ⁇ L), and prepare the above reaction on ice. Place the sample in a PCR instrument and set the program as follows: 37°C, 60 minutes; 95°C, 5 minutes; store at 4°C. The sample that completes the reaction is the cDNA sample.
  • Fluorescence quantitative PCR Use SYBR green staining to detect the transcription level of miR-124, and detect the transcription level of housekeeping gene U6 as an internal reference. Thaw all reagents required for small RNA SYBR green PCR kit to room temperature, dilute each cDNA sample template 10 times with RNase-free water, and then dilute 5 times. Prepare the reaction mixture according to Table 1 below, add the reaction mixture to a 96-well PCR plate, seal the plate with a sealing film, and filter. Perform the PCR reaction on a fluorescence quantitative PCR instrument according to the steps in Table 2.
  • Compound 1 upregulated miR-124 by 3.9 times (fold), and had good activity in promoting miR124 upregulation.
  • the product was defined as p-toluenesulfonate I crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG1 , and the positions of its characteristic peaks are shown in Table 4.
  • the DSC spectrum showed that the endothermic peak was 207.15°C.
  • DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 0.06%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.09%; under extreme conditions (i.e. 90% RH), the moisture absorption weight gain is about 0.23%. After DVS test, the crystal form was retested and the crystal form did not change.
  • the product was defined as phosphate I crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG2 , and the positions of its characteristic peaks are shown in Table 5.
  • the DSC spectrum showed that the endothermic peak was 164.15°C.
  • the product was defined as sulfate I crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG3 , and the positions of its characteristic peaks are shown in Table 6.
  • the DSC spectrum showed that the endothermic peaks were 196.39°C and 205.37°C.
  • the product was defined as sulfate II crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG4 , and the positions of its characteristic peaks are shown in Table 7.
  • the DSC spectrum showed that the endothermic peak was 212.61°C.
  • the TGA spectrum showed that the weight loss was 0.60% at 30°C-150°C.
  • DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 1.56%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 1.94%; under extreme conditions (i.e. 90% RH), the moisture absorption weight gain is about 4.11%. After DVS test, the crystal form was retested and the crystal form did not change.
  • the product was defined as sulfate III crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG5 , and the positions of its characteristic peaks are shown in Table 8.
  • the DSC spectrum showed that the endothermic peak was 123.93°C.
  • DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 0.66%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.76%; under extreme conditions (i.e. 90% RH), the moisture absorption weight gain is about 1.45%. After DVS test, the crystal form was retested and the crystal form did not change.
  • the product was defined as maleate I crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 6.
  • the position of its characteristic peaks is as follows: As shown in Table 9.
  • the DSC spectrum showed that the endothermic peak was 162.42°C.
  • the product was defined as maleate II crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG7 , and the positions of its characteristic peaks are shown in Table 10.
  • the DSC spectrum showed that the endothermic peak was 164.59°C.
  • DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 0.09%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.11%; under extreme conditions (i.e. 90% RH), the moisture absorption weight gain is about 1.11%.
  • the crystal form was retested after testing and the crystal form did not change.
  • the product was defined as hydrobromide salt form I by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG8 , and the positions of its characteristic peaks are shown in Table 11.
  • DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 0.04%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.06%; under extreme conditions (i.e. 90% RH), the moisture absorption weight gain is about 0.15%. After DVS test, the crystal form was retested and the crystal form did not change.
  • the product was defined as hydrochloride I crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 12.
  • the DSC spectrum showed that the endothermic peak was 173.40°C.
  • DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 0.33%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.37%; under extreme conditions (i.e. 90% RH), the moisture absorption weight gain is about 0.53%. After DVS test, the crystal form was retested and the crystal form did not change.
  • the product was defined as hydrochloride II crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 10 and the positions of its characteristic peaks are shown in Table 13.
  • the TGA spectrum showed that the weight loss was 0.40% at 30°C-120°C.
  • DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 0.08%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.12%; under extreme conditions (i.e. 90% RH), the moisture absorption weight gain is about 0.23%.
  • the crystal form was retested after testing and the crystal form did not change.
  • hydrobromide salt form I The hydrobromide salt form I, p-toluenesulfonate salt form I, hydrochloride salt form I, hydrochloride salt form II, maleate salt form II, phosphate salt form I and sulfate salt form II were spread out in the open and the stability of the samples was investigated under light (4500 Lux), high temperature (40°C, 60°C) and high humidity (RH75%, RH92.5%) conditions. The sampling period was 30 days.
  • hydrobromide salt form I p-toluenesulfonate salt form I
  • hydrochloride salt form I hydrochloride salt form II
  • maleate salt form II maleate salt form II
  • phosphate salt form I phosphate salt form I
  • sulfate salt form II were placed under 25°C/60% RH and 40°C/75% RH conditions, respectively, to investigate the stability.

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Abstract

本公开涉及一种喹啉胺类化合物的可药用盐、晶型及其制备方法。具体而言，本公开提供8-氯-N-（2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基）喹啉-2-胺的可药用盐、晶型及其制备方法，相应盐具备良好的稳定性，可更好地用于临床治疗。

Description

一种喹啉胺类化合物的可药用盐、晶型及其制备方法
本申请要求申请日为2022/11/25的中国专利申请2022114917754的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于制药领域，涉及一种喹啉胺类化合物的可药用盐、晶型及其制备方法。
背景技术
miR-124在全身各组织有广泛表达，尤其在脑部组织中高表达。研究表明，过表达miR-124可促进激活的巨噬细胞-小胶质细胞向静态转变，从而抑制自身免疫疾病脑脊髓炎。另外，miR-124可促进巨噬细胞向M2型转化，从而发挥抗炎作用。miR-124也影响T细胞分化，miR-124处理的T细胞IFN-γ和TNFα水平都有所下降。过表达miR-124通过下调STAT3蛋白，进而减少炎症细胞因子IL-17的表达，抑制Th17细胞的分化发挥抗炎作用。以上研究表明，发展一种新型的小分子药物，通过上调miR-124，可以用于有效地治疗相关炎症疾病。
公开的相关专利申请包括WO2010143169A2、WO2015001518A1、WO2016009065A2、WO2017158201A1和WO2020127843A1等。
WO2022247920公开了一类可上调miR-124的喹啉胺类化合物，结构如下所示，
成盐可改善药物某一些不理想的物理化学或生物学性质。开发出相对于8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺，在理化性质或药学性质方面具有更优异的性质的盐是具有重要意义的。鉴于固体药物晶型及其稳定性对其在临床治疗中的重要性，深入研究化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的可药用盐的多晶型，对开发适合工业生产且生物活性良好的药物也是具有重要意义。
发明内容
本公开一方面提供化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的可药用盐。
在一些实施方案中，其中所述可药用盐选自对甲苯磺酸盐、磷酸盐、硫酸盐、马来酸盐、氢溴酸盐和盐酸盐。
在另一些实施方案中，其中化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与酸分子的化学配比1:0.5～1:3，包括1:0.5、1:1、1:2或1:3。
在一些实施方案中，其中化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与酸分 子的化学配比1:0.5或1:1。
本公开另一方面还提供化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的可药用盐的制备方法，包括化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与酸成盐的步骤。
在一些实施方案中，成盐反应所用酸选自对甲苯磺酸、磷酸、硫酸、马来酸、氢溴酸盐和盐酸。
在一些实施方案中，成盐反应所用的溶剂选自乙醇、乙腈、丙酮、甲醇、水中的至少一种。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的对甲苯磺酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.616、8.996、14.120、19.138和22.592处有特征峰。
在一些实施方案中，所述对甲苯磺酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.616、8.996、14.120、17.120、19.138、20.615、22.592和25.033处有特征峰。
在一些实施方案中，所述对甲苯磺酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.616、8.996、13.304、14.120、17.120、19.138、20.615、21.289、22.592、25.033、26.101和26.503处有特征峰。
在另一些实施方案中，所述对甲苯磺酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
本公开还提供制备前述化合物的对甲苯磺酸盐I晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(1)混合，(b)加入对甲苯磺酸，析晶的步骤，其中溶剂(1)选自乙醇、丙酮、乙腈、甲醇、水中的至少一种。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的磷酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.511、9.685、12.660、14.012和15.704处有特征峰。
在一些实施方案中，所述磷酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.511、9.685、12.660、14.012、15.704、16.517、21.487和22.209处有特征峰。
在一些实施方案中，所述磷酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.511、9.685、12.660、14.012、15.704、16.517、18.507、21.487、22.209、24.493和25.596处有特征峰。
在另一些实施方案中，所述磷酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
本公开还提供制备前述化合物的磷酸盐I晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(2)混合，(b)加入磷酸，析晶的步骤，其中溶剂(2)选自乙腈。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的硫酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.687、11.448、14.670、17.315、23.323和24.907处有特征峰。
在一些实施方案中，所述硫酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.687、9.540、11.448、14.670、17.315、18.906、23.323和24.907处有特征峰。
在一些实施方案中，所述硫酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.687、9.540、11.448、12.137、14.670、17.315、17.465、18.906、21.682、23.323和24.907处有特征峰。
在另一些实施方案中，所述硫酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
本公开还提供制备前述化合物的硫酸盐I晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(3)混合，(b)加入硫酸，析晶的步骤，其中溶剂(3)选自乙醇或丙酮。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的硫酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在11.895、13.102、15.607、16.658和17.967处有特征峰。
在一些实施方案中，所述硫酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.518、11.895、13.102、15.607、16.181、16.658、17.967和24.329处有特征峰。
在一些实施方案中，所述硫酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.518、10.808、11.291、11.895、13.102、15.196、15.607、16.181、16.658、17.967和24.329处有特征峰。
在另一些实施方案中，所述硫酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
本公开还提供制备前述化合物的硫酸盐II晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(4)混合，(b)加入硫酸，析晶的步骤，其中溶剂(4)选自乙腈。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的硫酸盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.502、16.610、17.858、22.247和26.671处有特征峰。
在一些实施方案中，所述硫酸盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.675、13.502、16.610、17.858、22.247、25.379、26.671和27.029处有特征峰。
在一些实施方案中，所述硫酸盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.675、13.502、16.610、17.449、17.858、22.247、24.292、25.379、26.671和27.029处有特征峰。
在另一些实施方案中，所述硫酸盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
本公开还提供制备前述化合物的硫酸盐III晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(5)混合，(b)加入硫酸，析晶的步骤，其中溶剂(5)选自水与甲醇混合溶液。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的马 来酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.101、12.810、16.435、26.186和27.616处有特征峰。
在一些实施方案中，所述马来酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.101、12.810、16.435、20.667、25.309、26.186和27.616处有特征峰。
在一些实施方案中，所述马来酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.101、12.810、14.598、16.435、20.667、21.474、22.460、25.309、26.186和27.616处有特征峰。
在另一些实施方案中，所述马来酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
本公开还提供制备前述化合物的马来酸盐I晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(6)混合，(b)加入马来酸，析晶的步骤，其中溶剂(6)选自乙醇。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的马来酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.817、8.777、11.663、16.222和26.051处有特征峰。
在一些实施方案中，所述马来酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.817、8.777、11.663、12.691、16.222、21.791和26.051处有特征峰。
在一些实施方案中，所述马来酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.817、8.451、8.777、11.663、12.691、15.028、16.222、17.399、21.791和26.051处有特征峰。
在另一些实施方案中，所述马来酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本公开还提供制备前述化合物的马来酸盐II晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(7)混合，(b)加入马来酸，析晶的步骤，其中溶剂(7)选自乙腈、乙醇、甲醇或水的中至少一种。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的氢溴酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.077、12.258、22.769、24.662和26.579处有特征峰。
在一些实施方案中，所述氢溴酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.077、12.258、22.769、24.662、25.696、26.579和34.105处有特征峰。
在一些实施方案中，所述氢溴酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.077、12.258、16.589、20.396、22.769、24.662、25.218、25.696、26.579和34.105处有特征峰。
在另一些实施方案中，所述氢溴酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
本公开还提供制备前述化合物的氢溴酸盐I晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(8)混合，(b)加入氢溴酸，析晶的步骤，其中溶剂(8) 选自乙醇、乙腈或丙酮中的至少一种。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的盐酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.229、14.520、18.561、19.925和23.830处有特征峰。
在一些实施方案中，所述盐酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.229、14.520、18.561、19.925、23.830、24.603和25.325处有特征峰。
在一些实施方案中，所述盐酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.229、14.520、18.561、19.925、21.085、22.588、23.830、24.603、25.325和26.708处有特征峰。
在另一些实施方案中，所述盐酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
本公开还提供制备前述化合物的盐酸盐I晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(9)混合，(b)加入盐酸，析晶的步骤，其中溶剂(9)选自乙醇、乙腈或丙酮中的至少一种。
另一方面，本公开还提供了化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的盐酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在11.888、13.593、17.851、23.977和26.309处有特征峰。
在一些实施方案中，所述盐酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在11.888、13.593、17.851、19.114、23.977、25.878和26.309处有特征峰。
在一些实施方案中，所述盐酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在11.888、13.593、14.492、17.851、19.114、20.367、23.977、25.878、26.309和29.779处有特征峰。
在另一些实施方案中，所述盐酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
本公开还提供制备前述化合物的盐酸盐II晶型的方法，包括将化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺和溶剂(10)混合，(b)加入盐酸，析晶的步骤，其中溶剂(10)选自乙醇、甲醇或水中的至少一种。
进一步地，本公开前述化合物晶型，以衍射角2θ角度表示的X-射线粉末衍射图，其中2θ角度的误差范围为±0.2。
在某些实施方案中，本公开所述的晶型的制备方法还包括搅拌溶解或加热溶解、过滤、洗涤或干燥中任一步骤。
在一些实施方案中，所述析晶包括但不限于搅拌析晶(溶析析晶、打浆析晶)和挥发析晶。
在一些实施方案中，所述干燥方式包括但不限于鼓风干燥、真空干燥。干燥温度一般为25℃～100℃，优选30℃～70℃，如40℃、50℃或60℃。
另一方面，本公开还提供一种药物组合物，其包括前述晶型和药学上可接受的赋形剂。
本公开还提供一种药物组合物，由前述晶型和药学上可接受的赋形剂制备得到。
本公开还提供了一种药物组合物的制备方法，包括前述晶型与药学上可接受的赋形剂混合的步骤。
本公开还提供了前述晶型或药物组合物在制备用于调节miRNA水平的药物中的用途；优选地，所述miRNA为miR-124。
本公开还提供了前述晶型或药物组合物治疗和/或预防疾病或病况的药物中的用途，所述的疾病或病况选自炎症和癌症。
在一些实施方案中，所述炎症为炎性肠病。在一些实施方案中，所述癌症为黑色素瘤或乳腺癌。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20(包括超过1位小数的数字经过四舍五入后的情况)，具体为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开中所述干燥温度一般为25℃-100℃，优选30℃-70℃，可以常压干燥，也可以减压干燥。
本公开中所述的“药学上可接受的赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
本公开所述的“打浆”是指利用物质在溶剂中溶解性差，但杂质在溶剂中溶解性好的特性进行纯化的方法，打浆提纯可以去色、改变晶型或去除少量杂质。
本公开所述的晶型包括但不限于化合物1的溶剂合物，所述的溶剂包括但不限于水。
附图说明
图1为对甲苯磺酸盐I晶型XRPD图。
图2为磷酸盐I晶型XRPD图。
图3为硫酸盐I晶型XRPD图。
图4为硫酸盐II晶型XRPD图。
图5为硫酸盐III晶型XRPD图。
图6为马来酸盐I晶型XRPD图。
图7为马来酸盐II晶型XRPD图。
图8为氢溴酸盐I晶型XRPD图。
图9为盐酸盐I晶型XRPD图。
图10为盐酸盐II晶型XRPD图。
具体实施方式
通过以下实施例和实验例进一步详细说明本公开。这些实施例和实验例仅用于说明性目的，并不用于限制本公开的范围。
实验所用仪器的测试条件：
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)。waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q 15 Exactive)。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Thermo U3000高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，射线：单色Cu-Ka射线扫描方式：θ/2θ，扫描范围：3-48°。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，25-300℃，氮气吹扫速度50mL/min。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱，氮气吹扫速度50mL/min。
DVS为动态水分吸附：采用Surface Measurement Systems instrinsic，湿度从50％起，考察湿度范围为0％-95％，步进为10％，判断标准为每个梯度质量变化dM/dT≤0.002％，TMAX 360min，循环两圈。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1. 8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹-2-胺合成(参照申请号为WO2022247920的申请中实施例1的制备方法)
将2,8-二氯喹啉1a(100mg，0.51mmol，毕得医药)，5-氨基-2,2-二氟-1,3-苯并[1,3]二氧杂环戊烷1b(105mg，0.61mmol，上海皓鸿)溶解在异丙醇(1mL)中，加热升温至90℃反应12小时。反应液过滤后经高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：0.1％的甲酸水溶液和乙腈，乙腈的梯度：65％-85％，流速：30mL/min)得到标题化合物1(150mg，产率89.0％)。
MS m/z(ESI):335.0[M+1]。
1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.88(d,1H),8.17(d,1H),7.81(dd,1H),7.77(dd,1H),7.50(dd,1H),7.39(d,1H),7.32(t,1H),7.14(d,1H)。
测试例1.对miR-124的上调作用
一、实验材料及仪器
1.人T细胞活化CD3/CD28磁珠(Dynabead Human T-Activator CD3/CD28 for T Cell Expansion and Activation)(Gibco，11131D)
2.人总T细胞分离试剂盒(Pan T Cell Isolation Kit,human)(Miltenyi，130-096-535)
3.人白介素2(Human IL-2)(Peprotech，200-02-100)
4.小RNA抽提试剂盒(microRNA抽提试剂盒)(Qiagen，217004)
5.小RNA反转录试剂盒(miScript II RT Kit)(Qiagen，218161)
6.小RNA SYBR Green PCR试剂盒(miScript SYBR Green PCR Kit)(Qiagen，218073)
7.磷酸缓冲液PBS，pH7.4(上海源培生物科技股份有限公司，B320)
8.牛血清白蛋白，BSA(碧云天，ST023)
9.EDTA(0.5M),pH 8.0(Invitrogen，AM9260G)
10.LS分离柱(LS Columns)(Miltenyi,130-042-401)
11. 24孔细胞培养板(Corning，3524)
12. 96孔板(Corning，3788)
13.细胞培养箱(Thermo，Steri cycle i160)
14.实时荧光定量PCR仪(Applied biosystem，QuantStudio6Flex)
15.PCR仪(Applied biosystem，ProFlex)
16. 96孔透明PCR板，0.2mL(Applied biosystems，N8010560)
17.RPMI1640培养基(Gibco，11875119)
18.胎牛血清，FBS(Gibco，10099-141)
19.磁力架(Invitrogen，DynaMagTM-2)
20.六孔细胞培养板(Thermo，150239)
21.分光光度计(IMPLEN，NP80)
22.磁珠分离铁架(QuadroMACS Separator)(美天旎，130-090-976)
23.miR124-3P-F引物(金唯智公司定制)
24.hsa-U6检测引物(天根，CD201-0145)
二、实验步骤
化合物对miR-124表达水平的影响在CD3/CD28抗体激活后的T细胞中检测。激活的T细胞经过化合物处理后，提取细胞的总RNA，反转录所得的cDNA作为模板，使用特异性miR-124引物用SYBR green荧光定量PCR法来定量。
T细胞的分离：购买所得的人外周血单核细胞(PBMC)，计数过滤后用分离缓冲液(PBS pH 7.4,含有0.5％BSA和2mM EDTA))洗一遍，弃去上清，按每1×107个细胞加40μL缓冲液和10μL T细胞分离生物素化混合抗体(pan T Cell Biotin-Antibody Cocktail)的量，加入各成分重悬沉淀并混匀，4℃冰箱孵育5分钟。孵育完成后，按照每1×107个细胞加30μL缓冲液和20μL T细胞分离磁珠(Pan T Cell MicroBeads Cocktail)的量加入各成分，混匀后4℃冰箱孵育10分钟。用3毫升细胞分离缓冲液提前润洗分离柱子LS column，将上述细胞混悬液过柱，细胞悬液过柱后用1毫升细胞分离缓冲液重复洗柱子3遍，流出细胞液被收集在15毫升过滤管中即是富集的T细胞。对细胞进行计数，按1×106细胞/mL的密度加入含有10％FBS和40U/mL IL-2的RPMI1640培养基(完全培养基)，保存于冰上备用。
T细胞的活化：按每1×106个细胞加25μL活化磁珠的量，取出相应的T细胞活化CD3/CD28磁珠于1.5mL过滤管中，吸出前应在振荡器上振荡30s左右。在过滤管中以体积比大于1：1比例，使用培养基将活化磁珠洗3遍，最后一遍去除所有洗液，加入与起始体积等量的完全培养基重悬活化磁珠。将清洗好的活化磁珠加入细胞重悬液中，混合均匀。取出六孔板，以每孔3mL的量加入细胞，37℃，5％CO2细胞培养箱中培养2天。
化合物处理：化合物储存液为20mM，用DMSO稀释至200μM，再用完全培养基将化合物稀释4倍至50μM(50×)，混匀待用。DMSO稀释4倍(25％DMSO)为阴性对照孔。活化两天的T细胞，将细胞吹打均匀，使用磁力架并安装上1.5mL过滤管，去除活化磁珠，并收集细胞悬液。对细胞进行计数后，300xg，10min过滤弃上清，重悬细胞至1.02×106/mL，每个24孔板加入980μL细胞悬液和20μL 50×化合物，化合物最终浓度为1μM。将细胞置于37℃，5％CO2细胞培养箱中继续培养3天。
RNA抽提：将T细胞过滤收集，1500rpm过滤3分钟，PBS清洗1次，过滤后弃上清。使用小RNA抽 提试剂盒，根据说明书抽提细胞总RNA。细胞沉淀加入700μL Trizol细胞裂解液，枪头吹打均匀，于室温放置5分钟。加入140μL氯仿，振荡混匀，于室温静置3分钟。将氯仿-细胞裂解液混合物于4℃以12000xg过滤15分钟。将上层溶液转移至新的无RNA酶(RNase-free)的过滤管中，加入1.5倍体积的无水乙醇，枪头吹打数次。将溶液转移至RNA吸附柱中，8000xg过滤15s。将过滤柱用700μL RWT溶液洗一遍，8000xg过滤15s，加入500μL RPE溶液洗两遍，8000xg过滤2分钟。将吸附柱放入新的2mL过滤管中，12000xg过滤1min去除残余洗液。将吸附柱放入新的1.5mL过滤管中，加入30-50μL无RNA酶水(RNase-free water)，12000xg过滤2分钟，收集的溶液为RNA溶液，使用分光光度计测量RNA浓度。RNA溶液保存于-80度冰箱。
反转录：上述提取的RNA模板放置在冰上，取出小RNA反转录试剂盒，于室温解冻部分成分(包含5×miScript HiSpec Buffer，10×miScript nucleics Mix和无RNA酶水)，于冰上解冻miScript Reverse Transcriptase mix成分。每个反应(10μL)成分为：5×miScript HiSpec Buffer(2μL)，10×miScript nucleics Mix(1μL)，miScript Reverse Transcriptase mix(1μL)，无RNA酶水(2μL)，RNA模板(4μL)，在冰上配制上述反应。将样品放置于PCR仪中，设置程序如下：37℃，60分钟；95℃，5分钟；4℃保存。反应完成的样品为cDNA样品。
荧光定量PCR：使用SYBR green染色法检测miR-124的转录水平，同时检测管家基因U6的转录水平作为内参。解冻所有小RNA SYBR green PCR试剂盒所需试剂至常温，将每个cDNA样品模板用无RNA酶水稀释10倍，再稀释5倍。按照下表1配制反应混合物，并将反应混合物加入到96孔PCR板中，用封板膜封板，过滤。将PCR反应在荧光定量PCR仪上按照表2步骤进行。
表1荧光定量PCR反应成分表
表2荧光定量PCR步骤
表3荧光定量PCR检测引物表
数据分析：根据软件所算得的CT值，计算每个样品miR-124与内参U6表达水平的比值，即ΔCT(测试化合物)＝CTmiRNA-124(测试化合物)-CTU6(测试化合物)。相对表达量由以下公式计算，相对表达量(测试化合物)＝2(-[ΔCT(测试化合物)-ΔCT(DMSO)])。
化合物1miR-124上调(倍数)3.9倍，具有良好的促进miR124上调的活性。
实施例2：对甲苯磺酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL乙醇中，加入对甲苯磺酸溶液(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为对甲苯磺酸盐I晶型，XRPD谱图如图1，其特征峰位置如表4所示。
DSC谱图显示，吸热峰峰值207.15℃。
TGA谱图显示，30℃-150℃失重0.22％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.06％；在加速实验条件(即70％RH)，吸湿增重约为0.09％；在极端条件下(即90％RH)，吸湿增重约为0.23％。且DVS检测后复测晶型，晶型未转变。
表4
实施例3：对甲苯磺酸盐I晶型的制备
称取化合物1约10mg，加入0.15mL 10％水/甲醇，加入对甲苯磺酸溶液(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到标题产物。
实施例4：对甲苯磺酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL丙酮中，加入对甲苯磺酸溶液(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到标题产物。
实施例5：对甲苯磺酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL乙腈中，加入对甲苯磺酸溶液(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到标题产物。
实施例6：磷酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL乙腈中，加入磷酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为磷酸盐I晶型，XRPD谱图如图2，其特征峰位置如表5所示。
DSC谱图显示，吸热峰峰值164.15℃。
TGA谱图显示，30℃-140℃失重1.60％。
表5

实施例7：硫酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL乙醇中，加入硫酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为硫酸盐I晶型，XRPD谱图如图3，其特征峰位置如表6所示。
DSC谱图显示，吸热峰峰值196.39℃和205.37℃。
TGA谱图显示，30℃-150℃失重0.38％。
表6
实施例8：硫酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL丙酮中，加入硫酸(2mol/L，16.4μL)，搅拌析晶，离心 后固体真空干燥，得到标题产物。
实施例9：硫酸盐II晶型的制备
称取化合物1约10mg，溶于0.3mL乙腈中，加入硫酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为硫酸盐II晶型，XRPD谱图如图4，其特征峰位置如表7所示。
DSC谱图显示，吸热峰峰值212.61℃。
TGA谱图显示，30℃-150℃失重0.60％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为1.56％；在加速实验条件(即70％RH)，吸湿增重约为1.94％；在极端条件下(即90％RH)，吸湿增重约为4.11％。且DVS检测后复测晶型，晶型未转变。
表7

实施例10：硫酸盐III晶型的制备
称取化合物1约10mg，加入0.15mL 10％水/甲醇，加入硫酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为硫酸盐III晶型，XRPD谱图如图5，其特征峰位置如表8所示。
DSC谱图显示，吸热峰峰值123.93℃。
TGA谱图显示，30℃-100℃失重2.39％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.66％；在加速实验条件(即70％RH)，吸湿增重约为0.76％；在极端条件下(即90％RH)，吸湿增重约为1.45％。且DVS检测后复测晶型，晶型未转变。
表8
实施例11：马来酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL乙醇中，加入马来酸溶液(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为马来酸盐I晶型，XRPD谱图如图6，其特征峰位置如 表9所示。
DSC谱图显示，吸热峰峰值162.42℃。
TGA谱图显示，30℃-130℃失重0.62％。
表9
实施例12：马来酸盐II晶型的制备
称取化合物1约10mg，溶于0.15mL乙腈中，加入马来酸溶液(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为马来酸盐II晶型，XRPD谱图如图7，其特征峰位置如表10所示。
DSC谱图显示，吸热峰峰值164.59℃。
TGA谱图显示，30℃-145℃失重1.61％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.09％；在加速实验条件(即70％RH)，吸湿增重约为0.11％；在极端条件下(即90％RH)，吸湿增重约为1.11％。且DVS检 测后复测晶型，晶型未转变。
表10
实施例13：马来酸盐II晶型的制备
称取化合物1约10mg，加入0.15mL 10％水/甲醇，加入马来酸溶液(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到标题产物。
实施例14：马来酸盐II晶型的制备
称取化合物1约300mg，溶于4mL乙醇中，加入马来酸溶液(2mol/L，471μL)，搅拌析晶， 离心后固体真空干燥，得到标题产物。
实施例15：马来酸盐II晶型的制备
称取化合物1约10mg，溶于0.15mL乙醇中，加入马来酸溶液(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到标题产物。
实施例16：氢溴酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL乙醇中，加入氢溴酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为氢溴酸盐I晶型，XRPD谱图如图8，其特征峰位置如表11所示。
DSC谱图显示，吸热峰峰值228.04℃。
TGA谱图显示，30℃-150℃失重0.01％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.04％；在加速实验条件(即70％RH)，吸湿增重约为0.06％；在极端条件下(即90％RH)，吸湿增重约为0.15％。且DVS检测后复测晶型，晶型未转变。
表11

实施例17：氢溴酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL乙腈中，加入氢溴酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到标题产物。
实施例18：氢溴酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL丙酮中，加入氢溴酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到标题产物。
实施例19：盐酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL乙醇中，加入盐酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为盐酸盐I晶型，XRPD谱图如图9，其特征峰位置如表12所示。
DSC谱图显示，吸热峰峰值173.40℃。
TGA谱图显示，30℃-125℃失重4.16％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.33％；在加速实验条件(即70％RH)，吸湿增重约为0.37％；在极端条件下(即90％RH)，吸湿增重约为0.53％。且DVS检测后复测晶型，晶型未转变。
表12

实施例20：盐酸盐I晶型的制备
称取化合物1约200mg，溶于0.8mL丙酮中，加入浓盐酸(12mol/L，53μL)，搅拌析晶，离心后固体真空干燥，得到标题产物。
实施例21：盐酸盐I晶型的制备
称取化合物1约40mg，溶于0.2mL丙酮中，加入盐酸丙酮溶液(2mol/L，62.8μL)，搅拌析晶，离心后固体真空干燥，得到标题产物。
实施例22：盐酸盐I晶型的制备
称取化合物1约10mg，溶于0.15mL乙腈中，加入盐酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
实施例23：盐酸盐II晶型的制备
称取化合物1约10mg，加入0.15mL 10％水/甲醇，加入盐酸(2mol/L，16.4μL)，搅拌析晶，离心后固体真空干燥，得到产物。
经X-射线粉末衍射检测，将该产物定义为盐酸盐II晶型，XRPD谱图如图10，其特征峰位置如表13所示。
DSC谱图显示，吸热峰峰值172.83℃。
TGA谱图显示，30℃-120℃失重0.40％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.08％；在加速实验条件(即70％RH)，吸湿增重约为0.12％；在极端条件下(即90％RH)，吸湿增重约为0.23％。且DVS检 测后复测晶型，晶型未转变。
表13
测试例2：影响因素实验
将氢溴酸盐I晶型、对甲苯磺酸盐I晶型、盐酸盐I晶型、盐酸盐II晶型、马来酸盐II晶型、磷酸盐I晶型和硫酸盐II晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH75％、RH 92.5％)条件下样品的稳定性，取样考察期为30天。
表14：氢溴酸盐I晶型影响因素稳定性

表15：对甲苯磺酸盐I晶型影响因素稳定性
表16：盐酸盐I晶型影响因素稳定性

表17：盐酸盐II晶型影响因素稳定性
表18：马来酸盐II晶型影响因素稳定性

表19：磷酸盐I晶型影响因素稳定性
表20：硫酸盐II晶型影响因素稳定性
结论：影响因素实验表明，磷酸盐I晶型、硫酸盐II晶型、马来酸盐II晶型、盐酸盐II晶型、对 甲苯磺酸盐I晶型、氢溴酸盐I晶型物理和化学稳定性良好。
测试例3：长期加速稳定性考察
将氢溴酸盐I晶型、对甲苯磺酸盐I晶型、盐酸盐I晶型、盐酸盐II晶型、马来酸盐II晶型、磷酸盐I晶型和硫酸盐II晶型，分别放置25℃/60％RH和40℃/75％RH条件考察稳定性。
表21：氢溴酸盐I晶型长期加速稳定性
表22：对甲苯磺酸盐I晶型长期加速稳定性
表23：盐酸盐I晶型长期加速稳定性
表24：盐酸盐II晶型长期加速稳定性
表25：马来酸盐II晶型长期加速稳定性
表26：磷酸盐I晶型长期加速稳定性
表27：硫酸盐II晶型长期加速稳定性

Claims (18)

  1. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的可药用盐，其特征在于，所述可药用盐选自对甲苯磺酸盐、磷酸盐、硫酸盐、马来酸盐、氢溴酸盐和盐酸盐。
  2. 根据权利要求1所述的可药用盐，其特征在于，化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与酸分子的化学配比1:0.5～1:3，优选1:0.5、1:1、1:2或1:3，最优选1:0.5或1:1。
  3. 制备权利要求1或2所述的可药用盐的方法，其特征在于，包括化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺与酸成盐的步骤。
  4. 根据权利要求3所述的方法，其特征在于，成盐反应所用的溶剂选自乙醇、乙腈、丙酮、甲醇、水中的至少一种。
  5. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的对甲苯磺酸盐I晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.616、8.996、14.120、19.138和22.592处有特征峰，优选在6.616、8.996、14.120、17.120、19.138、20.615、22.592和25.033处有特征峰，更优选在6.616、8.996、13.304、14.120、17.120、19.138、20.615、21.289、22.592、25.033、26.101和26.503处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
  6. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的磷酸盐I晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.511、9.685、12.660、14.012和15.704处有特征峰，优选在6.511、9.685、12.660、14.012、15.704、16.517、21.487和22.209处有特征峰，更优选在6.511、9.685、12.660、14.012、15.704、16.517、18.507、21.487、22.209、24.493和25.596处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
  7. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的硫酸盐I晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.687、11.448、14.670、17.315、23.323和24.907处有特征峰，优选在5.687、9.540、11.448、14.670、17.315、18.906、23.323和24.907处有特征峰，更优选在5.687、9.540、11.448、12.137、14.670、17.315、17.465、18.906、21.682、23.323和24.907处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
  8. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的硫酸盐II晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在11.895、13.102、15.607、16.658和17.967处有特征峰，优选在6.518、11.895、13.102、15.607、16.181、16.658、17.967和24.329处有特征峰，更优选在6.518、10.808、11.291、11.895、13.102、15.196、15.607、16.181、16.658、17.967和24.329处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
  9. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的硫酸盐III晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.502、16.610、17.858、22.247和26.671处有特征峰，优选在8.675、13.502、16.610、17.858、22.247、25.379、26.671和27.029处有特征峰，更优选在8.675、13.502、16.610、17.449、17.858、22.247、24.292、25.379、26.671和27.029处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
  10. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的马来酸盐I晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.101、12.810、16.435、26.186和27.616处有特征峰，优选在8.101、12.810、16.435、20.667、25.309、26.186和27.616处有特征峰，更优选在8.101、12.810、14.598、16.435、20.667、21.474、22.460、25.309、26.186和27.616处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
  11. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的马来酸盐II晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.817、8.777、11.663、16.222和26.051处有特征峰，优选在7.817、8.777、11.663、12.691、16.222、21.791和26.051处有特征峰，更优选在7.817、8.451、8.777、11.663、12.691、15.028、16.222、17.399、21.791和26.051处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
  12. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的氢溴酸盐I晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.077、12.258、22.769、24.662和26.579处有特征峰，优选在6.077、12.258、22.769、24.662、25.696、26.579和34.105处有特征峰，更优选在6.077、12.258、16.589、20.396、22.769、24.662、25.218、25.696、26.579和34.105处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
  13. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的盐酸盐I晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.229、14.520、18.561、19.925和23.830处有特征峰，优选在13.229、14.520、18.561、19.925、23.830、24.603和25.325处有特征峰，更优选在13.229、14.520、18.561、19.925、21.085、22.588、23.830、24.603、25.325和26.708处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
  14. 化合物8-氯-N-(2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)喹啉-2-胺的盐酸盐II晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在11.888、13.593、17.851、23.977和26.309处有特征峰，优选在11.888、13.593、17.851、19.114、23.977、25.878和26.309处有特征峰，更优选在11.888、13.593、14.492、17.851、19.114、20.367、23.977、25.878、26.309和29.779处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
  15. 根据权利要求5-14任一项所述的晶型，其特征在于所述2θ值误差范围为±0.2。
  16. 一种药物组合物，其包括如权利要求1或2所述的可药用盐，或权利要求5-15任一项所述的晶型，和药学上可接受的赋形剂。
  17. 一种药物组合物，由如权利要求1或2所述的可药用盐，或权利要求5-15任一项所述的晶型和药学上可接受的赋形剂制备得到。
  18. 权利要求1或2所述的可药用盐，或权利要求5-15任一项所述的晶型，或权利要求16或17所述的药物组合物在制备用于治疗和/或预防疾病或病况的药物中的用途，所述的疾病或病况选自炎症和癌症，所述炎症优选炎性肠病，所述癌症优选黑色素瘤或乳腺癌。
PCT/CN2023/134049 2022-11-25 2023-11-24 一种喹啉胺类化合物的可药用盐、晶型及其制备方法 WO2024109937A1 (zh)

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JP2011026251A (ja) * 2009-07-27 2011-02-10 Kowa Co ２−アリールアミノキノリン化合物及びこれを有効成分として含有するエリスロポエチン産生促進剤
CN107207463A (zh) * 2014-07-17 2017-09-26 Abivax公司 用于治疗炎性疾病的喹啉衍生物
CN107531681A (zh) * 2015-02-23 2018-01-02 Abivax公司 用于治疗和预防病毒感染的新喹啉衍生物
CN112154144A (zh) * 2018-07-13 2020-12-29 江苏恒瑞医药股份有限公司 一种1,2,4-三嗪-3-胺类衍生物的晶型及制备方法
CN113825509A (zh) * 2018-12-20 2021-12-21 Abivax公司 用于治疗炎症疾病的喹啉衍生物
WO2022247920A1 (zh) * 2021-05-27 2022-12-01 江苏恒瑞医药股份有限公司 喹啉胺类化合物、其制备方法及其在医药上的应用

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JP2011026251A (ja) * 2009-07-27 2011-02-10 Kowa Co ２−アリールアミノキノリン化合物及びこれを有効成分として含有するエリスロポエチン産生促進剤
CN107207463A (zh) * 2014-07-17 2017-09-26 Abivax公司 用于治疗炎性疾病的喹啉衍生物
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